Stannane synthesis of prostanoids

ABSTRACT

The present invention is directed to novel methods of prostanoid synthesis. Specifically, the invention is directed to the addition of alpha chains to prostanoids using cis-alkenylstannane intermediates.

This application is a 371 of PCT/US99/19976 filed Sep. 1, 1999, whichclaims priority from Provisional application Ser. No. 60/103,235, filedOct. 5, 1998.

The present invention is directed to novel methods of prostanoidsynthesis. More specifically, the invention is directed to the additionof alpha chains to prostanoids using cis-alkenylstannane intermediates.

BACKGROUND OF THE INVENTION

Naturally occurring prostaglandins are biologically active in a myriadof ways including hormone action, muscular contraction/relaxation,platelet aggregation/inhibition, intraocular pressure reduction andother cellular transduction mechanisms. Prostaglandins are enzymaticallyproduced in nature from arachidonic acid. The arachidonic acid cascadeis initiated by the prostaglandin synthase catalyzed cyclization ofarachidonic acid to prostaglandin G₂ and subsequent conversion toprostaglandin H₂. Other naturally occurring prostaglandins arederivatives of prostaglandin H₂. A number of different types ofprostaglandins have been discovered including A, B, C, D, E, F andI-Series prostaglandins. These descriptions delineate substitutionpatterns of the various cyclopentane group central to allprostaglandins. Still other naturally occurring derivatives includethromboxane A2 and B2.

Due to their potent biological activity, prostaglandins have beenstudied for possible pharmaceutical benefit. However, due to potency ofthese molecules, as well as the ubiquitous presence of these agents andreceptors and other biologically responsive tissue sites to theirpresence, numerous side effects have prevented the exploitation of thenaturally occurring prostaglandins. It has also been difficult topharmaceutically exploit the naturally occurring prostaglandins due tothe relatively unstable nature of these molecules. As a result,researchers have been preparing and testing synthetic prostaglandinanalogs, also known as “prostanoids,” for several decades.

In general, prostanoids can be described generically as consisting of(1) an alpha chain; (2) an omega chain; and (3) a cyclopentane group (ora heterocycle or other ring structure), as shown in formula I.

In general, the E groups of the ring structure are independently O,CH—OH, C═O, CH-halogen and CH₂ groups. The omega chain has generallyconsisted of linear carbon backbones of varying lengths. The omegachains have also been of varying degrees of saturation, containingoptional hetero-atoms and have terminated with a variety of alkyl andcycloalkyl groups. Alpha chains have consisted of numerous linearmoieties and have involved various degrees of saturation. The alphachains generally consist of a seven carbon chain and generally terminatewith a carboxylic acid group or a variety of corresponding esters.

Of particular interest are a set of prostanoids having a double bond atcarbons 5 and 6 and an oxygen or carbon at the three position, accordingto formula II:

wherein, the E groups are as defined above; A is oxygen or carbon; Q isH or C₁₋₄ alkyl: and the omega chain (ω) is generally five to twelvecarbons in length with various substitutions including substitutions ofhetero-atoms within the chain.

As summarized in Scheme A, prostanoids of formula II can be prepared byreacting a methylene ketone 1 with a cis-alkenylcuprate 2 to install thealpha chain and thereby form the cis-alkenyl intermediate 3, wherein Xis O, CH₂, CH—OH (or CH—O-protected), ω is as defined above, R isgenerally a nontransferring group, R′ is generally a hydroxyl protectinggroup and Z′ is generally a masked carboxyl group.

The cis-alkenylcuprate 2a or 2b can be one of several different typesknown to those skilled in the art. Homocuprates bear two identicalcarbon groups bonded to copper, only one of which can efficiently form acarbon-carbon bond by transfer from copper, the remaining group being bydefinition the nontransferring group R. Heterocuprates bear twodifferent carbon groups bonded to copper, one of which (R) has a lowtendency to form a carbon-carbon bond compared with the transferringgroup, in this case the cis-alkenyl group. Higher-order cuprates containa metal cyanide salt, typically LiCN. Lower-order cuprates do notcontain metal cyanide salts but can contain other components capable ofmodifying reactivity, for example, a trialkylphosphine. Thecis-alkenylcuprates of formulas 2a and 2b are optionally associated witha metal cyanide salt or other component. See, generally, Lipshutz,Organic Reactions, volume 41, page 135 (1992).

Stork and Isobe, J. Am. Chem. Soc., volume 97, page 4745 (1975),disclose a method of preparing racemic 3-carba prostanoids as shown inScheme A, wherein X is CHOCH₂Ph (in the rel-R configuration), ω istrans-CH═CHCH(OCH₂OCH₂Ph)-n-C₅H₁₁, Z′ is CH₂OCH(Me)OEt, and thecis-alkenyl cuprate 2a is the lower-order homocupratecis-(EtOCH(Me)O(CH₂)₄CH═CH)₂CuLi.PBu3. The cis-alkenylcuprate 2a wasprepared from the cis-iodoalkene cis-EtOCH(Me)O(CH₂)₄CH═CHI bylithium-iodine exchange with tert-butyllithium, forming the intermediatecis-alkenyllithium compound cis-EtOCH(Me)O(CH₂)₄CH═CHLi, which was thenreacted with CuI—PBu₃ complex to yield 2a.

Sato, Tetrahedron: Asymmetry, volume 3, page 1525 (1992), discloses amethod of preparing nonracemic 3-oxa prostanoids as shown in Scheme A,wherein X is CHOSiMe₂t-Bu (in the R configuration), ω istrans-CH═CHCH(OSiMe₂t-Bu)-cyclo-C₆H₁₁ (in the S configuration), R′ isCH(Me)OEt, and the cis-alkenylcuprate 2b is the higher-orderheterocuprate cis-EtOCH(Me)OCH₂CH═CHCu(2-thienyl)Li.LiCN. Thecis-alkenylcuprate 2b was prepared from the cis-iodoalkenecis-EtOCH(Me)OCH₂CH═CHI by lithium-iodine exchange withtert-butyllithium, forming the intermediate cis-alkenyllithium compoundcis-EtOCH(Me)OCH₂CH═CHLi, which was then reacted with(2-thienyl)Cu(CN)Li to yield 2b.

The cis-iodoalkene to cis-alkenyllithium to cis-alkenylcuprate sequenceemployed in the foregoing examples has several disadvantages. Thepreparation of cis-iodoalkenes typically involves reaction of a1-iodoalkyne with diimide, which is not suitable for large scale workand always produces some 1-iodoalkane; see Luthy, J. Am. Chem. Soc.,volume 100, page 6211 (1978). Other methods of preparing cis-iodoalkenesgive variable amounts of the trans isomer, see Dieck, J. Org. Chem.,volume 40, page 1083 (1975), and Stork and Zhao, Tetrahedron Letters,volume 30, page 2173 (1989). The reagent of choice for converting thecis-iodoalkene to the cis-alkenyllithium has been tert-butyllithium,which is pyrophoric and not suitable for large scale work. Thisconversion must be performed at low temperature, typically −60° C. orbelow, in order to realize good yields.

Transmetalation methods have been described in the art. For example,U.S. Pat. No. 4,777,275 (Campbell et al.) discloses a directtin-to-copper transmetalation. In that disclosure, atrans-alkenylstannane is directly converted to a trans-alkenylcuprate,which is used for the addition of a trans omega chain to a prostanoid.

A need has arisen, therefore, to develop superior synthetic methods forthe preparation of the various prostanoids of interest, in greateryields.

SUMMARY OF THE INVENTION

The present invention is directed to methods of prostanoid synthesis.More specifically, the invention is directed to methods involvingcis-alkenylstannanes for prostanoid alpha chain addition.

The use of cis-alkenylstannanes obviates problems existing withtraditional synthetic methods involving treatment of cis-iodoalkeneswith alkyllithiums to form cis-alkenyllithiums, which are then convertedto cis-alkenylcuprates. The avoidance of the cis-iodoalkene andcis-alkenyllithium intermediates minimizes unwanted side products andalso allows for greater yield of key intermediates useful in prostanoidsynthesis.

Preferred methods of the present invention employ the novel intermediatesynthesis of the present invention in the synthesis of 3-oxaprostanoids.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to novel methods of prostanoidsynthesis. More specifically, the present invention is directed tomethods of improved prostanoid alpha chain addition to form prostanoidsof formula III:

wherein,

X is O, CH₂, C═O, or CH—OR⁴ in either configuration, or CH-halogen (F,Cl, Br, I) in either configuration;

A is CH₂ or O;

Q is H or C₁₋₄ alkyl;

R3 is H and one of: H, OR⁴, halogen, in either configuration, or, R3 is═O (i.e., carbonyl);

R⁴ is H, alkyl, acyl, or Si(R⁶)₃, wherein R⁶ is independently C₁₋₄ alkylor phenyl;

provided that when R3 is ═O, X is not CH-halogen, and when R3 is H andhalogen, X is not C═O;

ω is

 wherein:

---- is an optional bond;

D is H and one of: H, F or OR⁴, in either configuration; or D is ═O(i.e., carbonyl);

X¹ is (CH₂)_(m) or (CH₂)_(m)O, wherein m is 1 to 6; or X′ is CH—OH; and

Y is a phenyl ring optionally substituted with alkyl, halo,trihalomethyl, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, orhydroxy; or Y is C₁₋₆ alkyl or C₃₋₈ cycloalkyl, optionally substitutedwith C₁₋₆ alkyl, or

X¹—Y is (CH₂)_(p)Y′; wherein p is 0 to 6; and

 wherein:

W is CH₂, S(O)_(q), NR⁵, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(q), CH═N, orCH₂NR⁵;

wherein q is 0 to 2, and R⁵ is H, alkyl, or acyl;

Z is H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino,alkylamino, acylamino, or hydroxy; and

---- is an optional bond; or

X′—Y is C₁₋₆ alkyl, or C₃₋₈cycloalkyl.

Preferred prostanoids synthesized with the methods of the presentinvention are those of formula III having an ω chain consisting of:

wherein T is CF₃ or Cl, and R⁴ is defined as above. Most preferred arethose compounds wherein ⁴ is hydrogen.

The improved alpha addition methods of the present invention areillustrated in Scheme B.

wherein X is O, CH₂, CH—OH (or CH—O-protected), and 1, 3a, 3b, aredefined as is above.

The cis-alkenylcuprate 6a or 6b is prepared by transmetalation of acis-alkenylstannane 4a or 4b, respectively, by reaction with a cupratereagent 5. The R groups of 5 are chosen so that the transmetalation of 4to 6 proceeds efficiently, and so that in the subsequent reaction of 6with 1, the R group of 6 is a nontransferring group, for example analkyl group. The tin-to-copper transmetalation reaction can be performedin several different ways. For example, dilithium (dimethyl)cyanocuprate(5, R is methyl) can be reacted with the cis-alkenylstannane 7 in asolvent such as tetrahydrofuran, diethyl ether, an aromatic hydrocarbonor mixtures thereof. This reaction proceeds efficiently at a temperatureof about 0 to 25° C. The resulting cis-alkenylcuprate 6 is then reactedwith the exo-methylene ketone 1 to yield the cis-alkenyl intermediate 3.

For the preparation of 3-carba prostanoids, the cis-alkenylstannane 4ais of the formula cis-R″₃SnCH═CH(CH₂)₃Z′ wherein R″ is C₁ to C₆ alkyl,preferably methyl or n-butyl, and most preferably n-butyl, Z′ is afunctional group capable of being converted to COOH, and compatible withthe conditions of the tin-to-copper transmetalation reaction used toprepare the cis-alkenylcuprate 2a, for example, an ortho ester, acetal,or protected carbinol, as generally known to those skilled in the art.The compound cis-R″₃SnCH═CH(CH₂)₃Z′ can be prepared by the generalmethod described by Corey, Tetrahedron Letters, volume 25, page 2419(1984), involving copper-catalyzed coupling of cis-R″₃SnCH═CHCH₂OAc witha Grignard reagent (Hal)Mg(CH₂)₃Z′, wherein Hal=Cl, Br or I, and Z′ isdefined as above.

For the preparation of 3-oxa prostanoids, the cis-alkenylstannane 4b isof the formula cis-R″₃SnCH═CHCH₂OR′ wherein R″ is defined as above, andR′ is a protecting group compatible with the conditions of thetin-to-copper transmetalation reaction used to prepare thecis-alkenylcuprate 2b, for example, substituted silyl,tetrahydropyranyl, or 1-ethoxyethyl. The compound cis-R″₃SnCH═CHCH₂OR′can be prepared by appending a protecting group to cis-R″₃SnCH═CHCH₂OH,the preparation of which is known wherein R″ is n-butyl; see Corey,above. Alternatively, cis-R″₃SnCH═CHCH₂OR′ can be obtained byhydrozirconation of an alkynylstannane; see Lipshutz, TetrahedronLetters, volume 33, page 5861 (1992).

The cis-alpha chain intermediate 3b (generated from the novel methods ofthe present invention), can be converted to the 3-oxa prostanoids offormula III, wherein A is O, and R, R′R″ and ω are defined as above, byemployment of known methods in the art, for example, the sequencegenerally described by Sato, above, and as summarized in Scheme C,below. Accordingly, reduction of the keto group of 3b (wherein X isCHOSiMe₂t-Bu (in the R configuration), ω isCH₂CH₂CH(OSiMe₂t-Bu)-cyclo-C₆H₁₁ (in the R configuration), and R′ isCH(Me)OEt) gives alcohol 7. Removal of the protecting group CH(Me)OEt,from 7 (by known methods, e.g., Greene et al., Protective Groups inOrganic Synthesis, 2^(nd) ed., Wiley: New York, 1991) gives diol 8.Alkylation of 8 with tert-butyl bromoacetate gives the protected 3-oxaprostanoid 9. The OH group of 9 is substituted, via themethanesulfonate, with chloride to give the protected 9-chloro-3-oxaprostanoid 10. Removal of protecting groups from 10 provides the9-chloro-3-oxa prostanoid 11. Further processing can be employed to givean analog of 11 containing an alpha chain terminating ester of choice,preferably isopropyl ester.

As stated above, the methods of the present invention are also useful inpreparing the 3-carba prostanoids of formula III, wherein A is CH₂. Forexample, Stork and Isobe, above, disclose a method of converting acompound of Formula 3a, wherein X is CHOCH₂Ph (in the rel-Rconfiguration), ω is trans-CH═CHCH(OCH₂OCH₂Ph)C₅H₁₁ (in the rel-Sconfiguration) and Z′ is CH₂OCH(Me)OEt, into racemic prostaglandinF_(2α), i.e., the compound of formula III wherein A is CH₂, R3 is β-H,α-OH, X is CH—OH (in the rel-R configuration), Q is H and ω istrans-CH═CHCH(OH)-n-C₅H₁₁ (in the rel-S configuration). A furtherexample is shown in Scheme D. Reduction of the keto group of thecompound of formula 3a (wherein X is CHOSiMe₂t-Bu (in the Rconfiguration), ω is trans-CH═CHCH(OSiMe₂t-Bu)CH₂OC₆H₄-m-CF₃ (in the Rconfiguration), and Z′ is an OBO ester group (see Corey, above) givesalcohol 12. Hydrolysis of the OBO ester group of 12 yields the protected3-carba prostanoid 13. Removal of protecting groups from 13 yields thefree 3-carba prostanoid 14. Further processing can be employed to givean analog of 14 containing an alpha chain terminating ester of choice,preferably, isopropyl ester.

The following example further illustrates a preferred synthesis of thepresent invention:

EXAMPLE

The following is an example of the present invention: preparation of(2R,3R,4R)-2-[1′-[(2′Z)-4′-[(1-ethoxy)ethoxy]-2′-butenyl]-3-[1′-[(3′R)-3′-(t-butyldimethylsiloxy)-3′-cyclohexyl]-propyl]-4-(t-butyldimethylsiloxy)-cyclopentan-1-one.

Step 1

Preparation of (Z)-Bu₃SnCH═CHCH₂OCH(Me)OEt. (Z)-Bu₃SnCH═CHCH₂OH (Corey,above) was reacted with ethyl vinyl ether and catalytic pyridiniump-toluenesulfonate in dichloromethane to give(Z)-Bu₃SnCH═CHCH₂OCH(Me)OEt. NMR (CDCl₃) δ0.9 (m, 9H), 1.21 (t, J=7,3H), 1.2-1.7 (m, 18H), 1.33 (d, J=5, 3H), 3.4-3.75 (m, 2H), 3.85-4.3 (m,2H), 4.74 (q, J=5, 1H), 6.07 (1H, d, J=13; Sn satellites (13%), J=74),6.62 (1H, dt, J=13, 4.3; Sn satellites (13%), J=146).

Step 2

Preparation of(3R,4R)-2-methylene-3-[1′-[(3′R)-3-(t-butyldimethylsiloxy)-3′-cyclohexyl]-propyl]-4-(t-butyldimethylsiloxy)-cyclopentan-1-one.

(a) A solution of 4.25 g (25 mmol) of (R)-3-chloro-1-phenyl-1-propanolin 20 mL of methanol, containing 0.75 g of 5% rhodium-on-alumina, washydrogenated at 60-65 psig at RT on a Parr shaker for 6.5 hours. Thesolution was filtered and concentrated, and the crude product waspurified by chromatography on silica to give 2.32 g (55%) of(R)-3-chloro-1-cyclohexyl-1-propanol. NMR (DMSO-d₆) δ0.8-1.3 (m, 5H),1.5-1.9 (m, 6H), 3.30 (m, 1H), 3.68 (2 overlapping t, J=5.2 and 7.0,2H), 4.48 (d, J=5.9, 1H, exchanges).

(b) Ethyl vinyl ether (EVE) (10 mL) was added to a stirred, ice-cooledsolution of (R)-3-chloro-1-cyclohexyl-1-propanol (4.89 g, 27.7 mmol) andpyridinium p-toluenesulfonate (PPTS) (0.04 g) in 40 mL of dry CH₂Cl₂.After 10 minutes, 0.20 g of PPTS and 8 mL of EVE were added, and thesolution was allowed to warm to RT. After 1 hour, the solution wasfiltered through a pad of silica, eluting with diethyl ether.Concentration afforded 6.69 g (97%) of(R)-1-(3-chloro-1-cyclohexyl)propyl (1-ethoxyethyl) ether. NMR (CDCl₃)δ0.9-2.0 (m, 13H), 1.21 (t, J=7.0, 3H), 1.30 and 1.32 (2 overlapping d,J=5.3, 3H), 3.4-3.8 (m, 5H), 4.7 (2 overlapping q, J=5.3, 1H).

(c) Lithium wire (1% Na) (68 mg, 9.7 mg-atom) was added in 0.3-cm piecesto a stirred, cooled (0° C. internal) solution of4,4′-di-t-butylbiphenyl (2.66 g, 10.0 mmol) and 5 mg of 2,2′-bipyridylin 20 mL of dry tetrahydrofuran (THF) under argon. The mixture wastitrated to a red endpoint with n-BuLi (2.5 M in hexane, 0.12 mL) andstirred for 15 hours to form a deep blue-green solution of lithium4,4′-di-t-butylbiphenyl. The solution was cooled to −45° C. (internal),and a solution of(R)-1-(3-chloro-1-cyclohexyl)propyl(1-ethoxyethyl)ether (1.12 g, 4.5mmol) in 9.0 mL of dry hexane was added dropwise. After 5 minutes, asolution of 0.25 M lithium (2-thienyl)cyanocuprate in THF (20 mL) wasadded dropwise. After 10 minutes, a solution of(R)-2-((diethylamino)methyl)-4-(t-butyldimethylsiloxy)-2-cyclopentenone(1.12 g, 3.77 mmol) in 20 mL of dry THF was added dropwise. The solutionwas allowed to warm to −20° C. and was quenched into a rapidly stirredmixture of diethyl ether and saturated aqueous NH₄Cl. After four hours,the layers were separated and the aqueous solution was extracted withethyl acetate. The combined organic solutions were dried (MgSO₄),filtered and concentrated and the crude product was purified bychromatography on silica to give 0.95 g (57.5%) of(3R,4R)-2-methylene-3-[(3′R)-3′-(1-ethoxy)ethoxy)-3′-cyclohexyl-1′-propyl]-4-(t-butyldimethylsiloxy)cyclopentan-1-one.NMR (CDCl₃) δ0.06 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H), 0.8-1.9 (m, 15H),1.17 and 1.20 (2 overlapping t, J=7, 3H), 1.29 and 1.30 (2 overlappingd, J=5.3, 3H), 2.30 (A of ABX, Jab=18.0, Jax=4.6, 1H), 2.62 (B of ABX,Jab=17.8, Jbx=5.8, 1H), 2.65 (br s, 1H), 3.30 (br q, J=4, 1H), 3.55 (m,J=6, 2H), 4.12 (pent, J=5.2, 1H), 4.68 (2 overlapping q, J=5.2, 1H),5.29, 5.32 (both s, 2:3 ratio, total 1H), 6.08 (s, 1H).

(d) Pyridinium p-toluenesulfonate (0.25 g) was added to a stirredsolution of 3.2 g (7.3 mmol) of(3R,4R)-2-methylene-3-[(3′R)-3′-(1-ethoxy)ethoxy)-3′-cyclohexyl-1′-propyl]-4(t-butyldimethylsiloxy)cyclopentan-1-onein 50 mL of diethyl ether and 50 mL of i-PrOH at RT. After 2 hours, thesolution was poured into saturated aqueous NaHCO₃, and extracted withdiethyl ether and ethyl acetate. The combined organic solutions werewashed with water and brine, dried (MgSO₄), filtered and concentrated.The crude product was purified by chromatography on silica, giving 2.05g (77%) of(3R,4R)-2-methylene-3-((3′R)-3′-hydroxy-3′-cyclohexyl-1′-propyl)-4-(t-butyldimethylsiloxy)cyclopentan-1-one. NMR (DMSO-d₆) δ0.00 (s,3H), 0.01 (s, 3H), 0.79 (s, 9H), 0.8-1.8 (m, 15H), 2.11 (A of ABX,Jab=18.0, Jax=4.6, 1H), 2.65 (B of ABX, Jab=17.8, Jbx=5.8, 1H), 2.6 (brs, 1H), 3.10 (br s, 1H), 4.12 (br q, J=5, 1H), 4.21 (d, J=5.5, 1H,exchanges), 5.30 (s, 1H), 5.83 (s, 1H).

(e) To a stirred, ice-cooled solution of 1.53 g (4.2 mmol) of(3R,4R)-2-methylene-3-((3′R)-3′-hydroxy-3′-cyclohexyl-1′-propyl)-4-(t-butyldimethylsiloxy)cyclopentan-1onein 20 mL of dichloromethane and 15 mL of N,N-dimethylformamide underargon was added via syringe N-ethyldiisopropylamine (1.50 mL, 8.6 mmol)followed by t-butyldimethylsiyl triflate (2.0 mL, 8.7 mmol). After 1.5hours, the mixture was diluted with diethyl ether, extracted with water,then three times with saturated aqueous KH₂PO₄, water and brine, dried(MgSO₄), filtered and concentrated. The crude product was purified bychromatography on silica to give 1.60 g (80%) of(3R,4R)-2-methylene-3-[(3′R)-3′-(t-butyldimethylsiloxy)-3′-cyclohexyl-1′-propyl]-4-(t-butyldimethylsiloxy)cyclopentan-1-one.NMR (CDCl₃) δ0.02, 0.03, 0.06, 0.08 (each s, 3H), 0.88 (s, 18H), 0.9-1.8(m, 15H), 2.30 (A of ABX, Jab=18.0, Jax=4.6, 1H), 2.62 (B of ABX,Jab=17.8, Jbx=5.8, 1H), 2.63 (br s, 1H), 3.40 (br q, J=5, 1H), 4.09 (q,J=5.7, 1H), 5.28 (d, J=1.5, 1H), 6.08 (d, J=2.2, 1H).

Step 3

Preparation of(2R,3R,4R)-2-[1′-[(2′Z)-4′-[(1-ethoxy)ethoxy]-2′-butenyl]-3-[1′-[(3′R)-3′-(t-butyldimethylsiloxy)-3′-cyclohexyl]-propyl]-4-(t-butyldimethylsiloxy)-cyclopentan-1-one.

Under argon, methyllithium (0.80 mL of a 1 molar solution in 9:1cumene-tetrahydrofuran) was added dropwise to a stirred, ice-cooledsuspension of CuCN powder (36 mg, 0.40 mmol) in 1.0 mL of drytetrahydrofuran. After 5 min, (Z)—Bu₃SnCH═CHCH₂OCH(Me)OEt (0.16 g, 0.38mmol) (from Step 1) was added, rinsing with 0.5 mL of tetrahydrofuran.The solution was allowed to warm to room temperature and was stirred for1.5 hours, then cooled in a −78° C. bath. A solution of(3R,4R)-2-methylene-3-[1′-[(3′R)-3′-(t-butyldimethylsiloxy)-3′-cyclohexyl]-propyl]-4-(t-butyldimethylsiloxy)-cyclopentan-1-one(0.11 g, 0.23 mmol) (from Step 2) in 0.9 mL of dry tetrahydrofuran wasadded dropwise. After 10 min, the mixture was poured into saturatedaqueous NH₄Cl and stirred for several hours. The phases were separatedand the aqueous solution was extracted with ethyl acetate. The combinedorganic solutions were dried over MgSO₄, filtered and concentrated, andthe crude product was purified by chromatography on silica to afford0.10 g (72%) of(2R,3R,4R)-2-[1′-[(2′Z)-4′-[(1-ethoxy)ethoxy]-2′-butenyl]-3-[1′-[(3′R)-3′-t-butyldimethylsiloxy)-3′-cyclohexyl]-propyl]-4-(t-butyldimethylsiloxy)-cyclopentan-1-one.NMR (CDCl₃): δ0.02, 0.03, 0.05, 0.08 (each s, 3H), 0.89 (s, 18H),0.9-1.8 (m, 15H), 1.21 (t, J=7.0, 3H), 1.31 (t, J=5.3, 3H), 1.9 (br s,2H), 2.15 (A of ABX, Jab18.0, Jax=4.6, 1H), 2.59 (B of ABX, Jab=17.8,Jbx=5.8, 1H), 2.42 (br t, J=5.7, 2H), 3.39 (br q, J=5, 1H), 3.6 (m, 2H),4.1 (m, 3H), 4.72 (q, J=5.3, 1H), 5.6 (m, 2H).

The(2R,3R,4R)-2-[1′-[(2′Z)-4′-[(1-ethoxy)ethoxy]-2′-butenyl]-3-[1′-[(3′R)-3′-(t-butyldimethylsiloxy)-3′-cyclohexyl]-propyl]-4-(t-butyldimethylsiloxy)-cyclopentan-1-oneproduct of the above Example can now be used in various prostanoidsyntheses known to those skilled in the art. For example, the productmay be inserted in Scheme C or D for the preparation of 3-oxa or 3-carbaprostanoids, respectively. Other examples of prostanoid synthesis forwhich the product would be a useful intermediate include methodsdisclosed in commonly assigned U.S. patent application Ser. No.08/167,470, filed Dec. 15, 1993.

By employment of known methods in the art, for example, the sequencegenerally described by Sato, above, the(2R,3R,4R)-2-[1′-[(2′Z)-4′-[(1-ethoxy)ethoxy]-2′-butenyl]-3-[1′-[(3′R)-3′-(t-butyldimethylsiloxy)-3′-cyclohexyl]-propyl]-4-(t-butyldimethylsiloxy)-cyclopentan-1-one product of the above Example can be converted to(5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoicacid.

I claim:
 1. A method for preparing prostanoids of formula (III)

wherein, X is O, CH₂, C═O, or CH—OR⁴ in either configuration, orCH-halogen (F, Cl, Br, I) in either configuration; A is O; Q is H orCl₁₋₄ alkyl; R3 is H and one of: H, OR⁴, halogen, in eitherconfiguration, or, R3 is O; R⁴ is H, alkyl, acyl, or Si(R⁶)₃, wherein R⁶is independently C₁₋₄ alkyl or phenyl; provided that when R3 is O, X isnot CH-halogen, and when R3 is H and halogen, X is not C═O; ω is

 wherein: ---- is an optional bond; D is H and one of: H, F or OR⁴, ineither configuration; or D is O; X′ is (CH₂)_(m) or (CH₂)_(m)O, whereinm is 1 to 6; or X′ is CH—OH; and Y is a phenyl ring optionallysubstituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy,amino, alkylamino, acylamino, or hydroxy; or Y is C₁₋₆ alkyl or C₃₋₈cycloalkyl, optionally substituted with C₁₋₆ alkyl, or X′—Y is(CH₂)_(p)Y′; wherein p is 0 to 6; and

 wherein: W is CH₂, O, S(O)_(q), NR⁵, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(q),CH═N, or CH₂NR⁵; wherein q is 0 to 2, and R⁵ is H, alkyl, or acyl; Z isH, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino,acylamino, or hydroxy; and ---- is an optional bond; or X¹—Y is C₁₋₆alkyl, or C₃₋₈ cycloalkyl, comprising the steps of: (a) reacting acompound of formula (IV):

 wherein, R¹¹ is C₁-C₆ alkyl and R¹ is alkyl, arylalkyl, alkoxyalkyl orsubstituted silyl, with a compound of formula (V): R₂CuLi.LiCN  (V) wherein R is C₁-C₆ alkyl, to form a product of formula (VI):

(b) reacting the product (VI) with a compound of the formula (VII):

 to form a compound of formula (III), wherein is A is O.
 2. A method forpreparing 3-carba prostanoids of formula (III):

wherein, X is O, CH₂, C═O, or CH—OR⁴ in either configuration, orCH-halogen (F, Cl, Br, I) in either configuration; A is CH₂; Q is H orC₁₋₄ alkyl; R3 is H and one of: OR⁴, halogen, H, in eitherconfiguration, or, R3 is O; R⁴ is H, alkyl, acyl, or Si(R⁶)₃, wherein R⁶is independently C₁₋₄ alkyl or phenyl; with the proviso that if R3 is Othen X is not CH-halogen, and that if R3 is CH-halogen then X is notC═O; ω is

 wherein: ---- is an optional bond; D is H and one of: H, F or OR⁴, ineither configuration; or D is O; X′ is (CH₂)_(m) or (CH₂)_(m)O, whereinm is 1 to 6; or X′ is CH—OH; and Y is a phenyl ring optionallysubstituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy,amino, alkylamino, acylamino, or hydroxy; or Y is C₁₋₆ alkyl or C₃₋₈cycloalkyl, optionally substituted with C₁₋₆ alkyl, or X′—Y is(CH₂)_(p)Y′; wherein p is 0 to 6; and

 wherein: W is CH₂, O, S(O)_(q), NR⁵, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(q),CH═N, or CH₂NR⁵; wherein q is 0 to 2, and R⁵ is H, alkyl, or acyl; Z isH, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino,acylamino, or hydroxy; and ---- is an optional bond; or X¹—Y is C₁₋₆alkyl, or C₃₋₈ cycloalkyl, comprising the steps of: (a) reacting acompound of formula (VIII):

 wherein, R¹¹ is C₁₋₆ alkyl and Z¹ is CH₂OR¹, CH(O-alkyl)₂ orC(O-alkyl)₃, and R¹ is alkyl, arylalkyl, alkoxyalkyl or substitutedsilyl, with a compound of formula (V): R₂CuLi.LiCN  (V)  wherein R isC₁₋₆ alkyl, to form a product of formula (IX):

(b) reacting the product (IX) with a compound of the formula (VII):

 to form a compound of formula (III), wherein A is CH₂.